A randomized study of the safety and pharmacokinetics of GSK3358699, a mononuclear myeloid-targeted bromodomain and extra-terminal domain inhibitor.

AIMS: GSK3358699 is a mononuclear myeloid-targeted bromodomain and extra-terminal domain (BET) family inhibitor which demonstrates immunomodulatory effects in vitro. This phase 1, randomized, first-in-human study evaluated the safety, pharmacokinetics, and pharmacodynamics of GSK3358699 in healthy male participants (NCT03426995). METHODS: Part A (N = 23) included three dose-escalating periods of 1-40 mg of GSK3358699 or placebo in two cohorts in a single ascending-dose crossover design. Part C (N = 25) was planned as an initial dose of 10 mg of GSK3358699 or placebo daily for 14 days followed by selected doses in four sequential cohorts. RESULTS: In part A, exposure to GSK3358699 and its metabolite GSK3206944 generally increased with increasing doses. The median initial half-life ranged from 0.7 to 1.1 (GSK3358699) and 2.1 to 2.9 (GSK3206944) hours after a single dose of 1-40 mg. GSK3206944 concentrations in monocytes were quantifiable at 1-hour post-dose following 10 mg of GSK3358699 and 1 and 4 hours post-dose following 20-40 mg. Mean predicted percentage inhibition of ex vivo lipopolysaccharide-induced monocyte chemoattractant protein (MCP)-1 reached 75% with 40 mg of GSK3358699. GSK3358699 did not inhibit interleukin (IL)-6 and tumour necrosis factor (TNF). The most common adverse event (AE) was headache. Four AEs of nonsustained ventricular tachycardia were observed across parts A and C. One serious AE of atrial fibrillation (part C) required hospitalization. CONCLUSIONS: Single doses of GSK3358699 are generally well tolerated with significant metabolite concentrations detected in target cells. A complete assessment of pharmacodynamics was limited by assay variability. A causal relationship could not be excluded for cardiac-related AEs, resulting in an inability to identify a suitable repeat-dose regimen and study termination.

Epithelial desquamation observed in a phase I study of an oral cathepsin C inhibitor (GSK2793660).

AIMS: Cathepsin C (CTSC) is necessary for the activation of several serine proteases including neutrophil elastase (NE), cathepsin G and proteinase 3. GSK2793660 is an oral, irreversible inhibitor of CTSC that is hypothesized to provide an alternative route to achieve NE inhibition and was tested in a Phase I study. METHODS: Single escalating oral doses of GSK2793660 from 0.5 to 20 mg or placebo were administered in a randomized crossover design to healthy male subjects; a separate cohort received once daily doses of 12 mg or placebo for 21 days. Data were collected on safety, pharmacokinetics, CTSC enzyme inhibition and blood biomarkers. RESULTS: Single, oral doses of GSK2793660 were able to dose-dependently inhibit whole blood CTSC activity. Once daily dosing of 12 mg GSK2793660 for 21 days achieved ≥90% inhibition (95% CI: 56, 130) of CTSC within 3 h on day 1. Only modest reductions of whole blood enzyme activity of approximately 20% were observed for NE, cathepsin G and proteinase 3. Seven of 10 subjects receiving repeat doses of GSK2793660 manifested epidermal desquamation on palmar and plantar surfaces beginning 7-10 days after dosing commencement. There were no other clinically important safety findings. CONCLUSIONS: GSK2793660 inhibited CTSC activity but not the activity of downstream neutrophil serine proteases. The palmar-plantar epidermal desquamation suggests a previously unidentified role for CTSC or one of its target proteins in the maintenance and integrity of the epidermis at these sites, with some similarities to the phenotype of CTSC-deficient humans.

Pharmacokinetics and pharmacodynamics of intravenous and inhaled fluticasone furoate in healthy Caucasian and East Asian subjects.

AIM: The aim of the study was to evaluate the pharmacokinetics (PK) of inhaled and intravenous (i.v.) fluticasone furoate (FF) in healthy Caucasian, Chinese, Japanese and Korean subjects. METHOD: This was an open label, randomized, two way crossover study in healthy Caucasian, Chinese, Japanese and Korean subjects (n = 20 per group). Inhaled FF (200 µg for 7 days, then 800 µg for 7 days from a dry powder inhaler [DPI]) was administered in one treatment period and i.v.FF (250 µg infusion) in the other. FF PK and serum cortisol (inhaled 200 µg only) were compared between the ethnic groups using analysis of variance. P450 CYP3A4 activity and safety were also assessed. RESULTS: Ethnic differences in i.v. FF PK were accounted for by body weight differences. CYP3A4 activity was similar across the groups. Higher FF systemic exposure was seen following inhaled dosing in Chinese, Japanese and Korean subjects compared with Caucasian subjects. Absolute bioavailability was greater (36%-55%) in all East Asian groups than for Caucasian subjects following inhaled FF 800 µg. Deconvolution analysis suggested inhaled FF resided in the lung of East Asian subjects longer than for Caucasians (time for 90% to be absorbed [t90]: 29.1-30.8 h vs. 21.4 h). In vitro simulation method predicted comparable delivered lung dose across ethnic groups. Serum cortisol weighted mean was similar between Caucasians and Chinese or Koreans, while in Japanese was on average 22% lower than in Caucasians. All FF treatments were safe and well tolerated. CONCLUSION: Modestly higher (<50%) FF systemic exposure seen in East Asian subjects following inhaled dosing was not associated with a clinically significant effect on serum cortisol, suggesting that a clinical dose adjustment in East Asian subjects is not required.

The effect of ketoconazole on the pharmacokinetics and pharmacodynamics of inhaled fluticasone furoate and vilanterol trifenatate in healthy subjects.

AIM: To investigate the effects of the cytochrome P450 3A4 (CYP3A4) inhibitor ketoconazole on the pharmacokinetics (PK) and pharmacodynamics of fluticasone furoate (FF) and vilanterol trifenatate (VI). METHODS: Two double-blind, randomized, placebo-controlled, two-way crossover studies in healthy subjects. In study 1, subjects received single doses of ketoconazole (400 mg) or placebo on days 1-6, with a single dose of inhaled VI (25 µg) on day 5. Pharmacodynamic and PK data were obtained up to 48 h following the VI dose. In study 2, subjects received once daily ketoconazole (400 mg) or placebo for 11 days, with FF/VI (200/25 µg) for the final 7 days. Pharmacodynamic and PK data were obtained up to 48 h following the day 11 dose. RESULTS: In study 1, there was no effect of co-administration of ketoconazole and VI on pharmacodynamic or PK parameters. In study 2, co-administration of ketoconazole and FF/VI had no effect on 0-4 h maximal heart rate or minimal blood potassium {treatment difference [90% confidence interval (CI)] -0.6 beats min(-1) (-5.8, 4.5) and 0.04 mmol l(-1) (-0.03, 0.11), respectively}, whilst there was a 27% decrease in 24 h weighted mean serum cortisol [treatment ratio (90% CI) 0.73 (0.62, 0.86)]. Co-administration of ketoconazole increased [percentage change (90% CI)] FF area under the curve (0-24) and maximal plasma concentration by 36% (16, 59) and 33% (12, 58), respectively, and VI area under the curve (0-t') and maximal plasma concentration by 65% (38, 97) and 22% (8, 38), respectively. CONCLUSION: Co-administration of FF/VI or VI with ketoconazole resulted in a less than twofold increase in systemic exposure to FF and VI. There was no increase in ß-agonist systemic pharmacodynamic effects, while serum cortisol was decreased by 27%. Co-administration of FF/VI with strong CYP3A4 inhibitors has the potential to increase systemic exposure to both fluticasone furoate and vilanterol, which could lead to an increase in the potential for adverse reactions.

The efficacy of once-daily fluticasone furoate/vilanterol in asthma is comparable with morning or evening dosing.

AIM: To investigate the effect of time of day of dosing (morning or evening) on lung function following administration of fluticasone furoate (FF)/vilanterol (VI) 100/25 mcg. METHODS: Double-blind, placebo-controlled, randomised, three-way crossover study. Subjects with persistent asthma (N = 26) received FF/VI (morning or evening) or matching placebo once-daily for 14 (± 2 days) via dry powder inhaler (DPI). Weighted mean (0-24h) and pre-treatment FEV1 (morning and evening) were determined after the Day 14 evening dose, together with mean pre-treatment (morning and evening) peak expiratory flow (PEF) on Days 2-12. RESULTS: FF/VI 100/25 administered morning or evening produced clinically significant increases in weighted mean FEV1: the differences [95% confidence interval (CI)] from placebo were 377 mL [293, 462] and 422 mL [337, 507], respectively; the difference between morning and evening dosing was -44 mL [-125, 36]. Day 14 pre-treatment morning FEV1 differences [95% CI] from placebo were 403 mL [272, 533] and 496 mL [369, 624] after morning and evening dosing, respectively; the morning:evening treatment difference was -94 mL [-221, 34]. Pre-treatment evening FEV1 differences [95% CI] from placebo were 275 mL [169, 380] and 309 mL [205, 413] after morning and evening dosing, respectively; the morning:evening treatment difference was -34 mL [-138, 70]. FF/VI (morning or evening) produced rapid increases in PEF with the full effect apparent after the first dose and maintained throughout the 14-day treatment period. CONCLUSION: FF/VI 100/25 produces comparable improvements in lung function whether dosed in the morning or evening in subjects with persistent asthma.